The present invention relates to a method for the production of ester compounds that are represented by the formula (I)
or salts thereof, where X stands for a halogen radical, R1 and R2 are selected so that (1) R1 is H and R2 is —CH2(CH2)mCOOR3, (2) R1 is —CH2(CH2)mCOOR3 and R2 is H or (3) R1 and R2 together stand for a radical represented by the formula (II)
where each of R3, R4 and R5 stands independently for an alkyl radical, and where each of m and n represents independently a number in the range of 0-12. The present invention likewise relates to a method for the production of the correspondingly hydrolyzed ester, i.e., a compound represented by the formula (VII)
or a salt thereof, where X stands for a halogen radical, R11 and R12 are selected so that (1) R11 is H and R12 is —CH2(CH2)mCOOH, (2) R11 is CH2(CH2)mCOOH and R12 is H or (3) R11 and R12 together stand for a radical represented by the formula (VIII)
where R4 stands for an alkyl radical and where each of m and n represents independently a number in the range of 0-12.
Compounds having the structure according to formula (VII) named above are used for chemotherapy for various cancers. Their effect involves the alkylation of endogenous DNA or RNA, which leads, in particular, to a prevention of DNA replication and consequently to apoptosis of the corresponding cells. The fields of use of the mentioned compounds comprise primarily the treatment of various leukemias and lymphomas, multiple myeloma, and bronchial carcinoma. Structurally, these compounds are derived from nitrogen mustard.
Bendamustine 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazole-2-yl]butanoic acid, which is a representative of this group, was first described in 1963 by Ozegowski and Krebs (J. Pract. Chem., 20: 178-86 (1963)).
One advantageous method for the production of bendamustine is known from German Democratic Republic Patent DD 34727. The synthesis disclosed therein is carried out via the corresponding bendamustine ester, 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazole-2-yl]butanoic acid ester, which is produced by the chlorination of 4-[5-[bis(2-hydroxyethyl)amino]-1-methylbenzimidazole-2-yl]butanoic acid ester. Thionyl chloride is used for the substitution of the two terminal hydroxyl groups of this starting compound by chlorine. Bendamustine can actually be obtained in significant quantities with the method described in DD 34727. A disadvantage in this method, however, is that bendamustine is delivered in very unsteady yields that also fall significantly even if the starting materials are increased.
To solve this problem, it is proposed in German Democratic Republic Patent DD 159877 to stir the reaction mixture of thionyl chloride and 4-[5-[bis(2-hydroxyethyl)amino]-1-methylbenzimidazole-2-yl]butanoic acid ester for the termination of the reaction directly in aqueous hydrochloric acid, whereby the excess thionyl chloride is broken down. Through this measure, a quantitative increase in the yields of bendamustine ester and finally also bendamustine can be achieved.
In further tests, however, it has been shown that even with the method of DD 159877, an increase of the yield of bendamustine ester or bendamustine to greater than 80% is not to be achieved. In addition, it was determined that, in the case of this method, byproducts are produced that can be separated from bendamustine ester or bendamustine only with difficulty and thus negatively influence the product quality. The resulting yields of bendamustine ester or bendamustine also cannot be obtained in a reproducible way, but instead fluctuated considerably despite maintaining the same test conditions. This was shown, in particular, in the test to carry out the method of DD 159877 on an industrial scale. Here, the control of the reaction proved to be difficult due to the high required excess of thionyl chloride. Another problem is produced from the viewpoint of processing economics due to the fact that, when thionyl chloride is used, large quantities of acidic process exhaust gases are generated, placing high demands on the exhaust-gas purification. Similar problems result when the method of DD 159877 is transferred to the production of other compounds that can be represented by the formulas (I) or (VII).